Pulsatile drug delivery system for treating morning akinesia

ABSTRACT

Provided herewith is a pharmaceutical composition comprising, separately or together, a pulsatile release component comprising levodopa and a DOPA decarboxylase inhibitor for the management of OFF-time episodes in patients with Parkinson&#39;s disease.

TECHNICAL FIELD

The present invention relates to a pulsatile drug delivery system thatenables a delayed burst release of levodopa and DOPA decarboxylaseinhibitors including carbidopa in the small intestine, thereby providingfor improved management of morning akinesia in Parkinson's diseasepatients.

BACKGROUND

Movement disorders are frequently caused by impaired regulation ofdopamine neurotransmission. Parkinson's disease (PD) is an example of amovement disorder associated with dysfunctional regulation of dopamineneurotransmission, which is caused by progressive degeneration ofdopamine neurons. In order to replace the lost dopamine PD motorsymptoms is currently treated with oral levodopa (L-DOPA, a precursor ofdopamine), which must be emptied from the stomach and absorbed in theproximal small intestine. Levodopa is converted into dopamine in thebrain, and stored in the neurons until needed by the body for movement.It remains the single most effective agent in the management ofParkinson's symptoms.

Most PD patients treated with levodopa have motor fluctuations. Animprovement in symptoms after L-DOPA administration is defined as “ON”,whereas a return to symptoms is termed “OFF”, i.e. when levodopa plasmaconcentration decreases. OFF periods generally appear when the benefitfrom a given levodopa dose disappears prematurely (wearing OFF) or whenthe next L-DOPA dose produces a delayed onset of action (delayed ON).

Motor complications of PD have been reported to occur after a few yearsof treatment with levodopa, whereby the long duration response becomesreplaced by a short duration response, and OFF periods emerge. While OFFperiods can be treated with several adjunctive medications, delayedonset of the next levodopa dose can significantly increase OFF periodduration.

Morning akinesia is a delayed ON of the first L-DOPA daily dose,occurring in almost 60% of patients on dopaminergic treatment. This isprimarily a motor symptom, but has been recently recognized as beingcorrelated with nonmotor fluctuations.

Morning akinesia can significantly affect quality-of-life in PDpatients, impairing the ability to perform basic daily activities.

Standard oral levodopa treatment is inadequate for the treatment ofmorning akinesia for reasons related to its pharmacodynamics andpharmacokinetics and because of its short half-life, erraticgastrointestinal absorption, and competitive transport across theblood-brain barrier. One of the first strategies attempted to focus onprolonging levodopa plasma levels, using long-acting, controlled-releaselevodopa preparations. Nevertheless, due to delayed gastric emptying, anoral dose of L-DOPA may remain in the stomach for a long time beforebeing absorbed in the small intestine. Another approach is administeringlevodopa as a liquid solution to reduce gastric transit time and improvethe onset of effect. This approach may be beneficial for some patientswith severe fluctuations; however, the clinical benefits of liquidlevodopa compared with tablets have not been confirmed in controlledclinical studies. To manage early morning akinesia and episodes ofnocturnal hypomobility, many patients use L-DOPA on an intermittent oras-needed basis. However, the slow or unpredictable onset of effectlimits the clinical benefit.

Alternative delivery of dopaminergic therapy by a non-oral route, suchas subcutaneous apomorphine injection is used by patients with PD in theOFF state to decrease time-to-ON. However, an early morning subcutaneousself-pen injection in disabled advanced PD patients could betroublesome. Nasal, pulmonal and sublingual formulations of levodopa arealso available.

Levodopa is almost always given in combination with DOPA decarboxylaseinhibitors such as carbidopa that prevents the breakdown of levodopabefore it can reach the brain and take effect; carbidopa enables a muchlower dose of levodopa (80% less) and helps reduce the side effects ofnausea and vomiting. Carbidopa/levodopa tablets are available inimmediate-release (IR) and extended-release (ER) forms as well asdissolvable tablets that are placed under the tongue. A small, portableinfusion pump delivers carbidopa and levodopa directly into the smallintestine.

ER combination formulations maintain plasma levodopa concentrations inthe therapeutic window for a prolonged time, providing greater ON timefor patients and better home management and mobility; but it has notbeen established that the ER formulation improves dyskinesias or totalsickness impact profile (SIP) scores.

It has been suggested that pretreatment with carbidopa prior to levodopain some instances increases levodopa plasma AUC compared to simultaneousadministration (see e g. Leppert et al. 1988).

Morning akinesia is one of the most common and earliest motorcomplications in PD patients, affecting almost all stages of thedisease. There remains an unmet medical need to improve the night timesleeping pattern and morning akinesia in patients with Parkinson'sdisease in a safe, non-invasive and compliant manner.

SUMMARY

The present inventors have developed a pharmaceutical composition thataddresses short-comings of current formulations comprising levodopa andDOPA decarboxylase inhibitors; by providing a composition that enablestimed pulsatile release of these compounds. Providing a delayed burstrelease of a DOPA decarboxylase inhibitor such as carbidopa and adelayed burst release of levodopa after a predetermined lag time,preferably separated in time whereby the DOPA decarboxylase inhibitor isreleased before levodopa, provides a means for the management of morningakinesia in patients with Parkinson's disease.

With the disclosed pulsatile drug delivery, the patient may improve thenight time sleeping pattern and be efficiently relieved from a completedisabling state in the morning. Furthermore, such a composition can betaken together with existing marketed immediate and controlled releaselevodopa products, to provide a full day dose coverage for most patientswith Parkinson's disease.

It is an aspect to provide a pulsatile release pharmaceuticalcomposition comprising

-   -   a. levodopa and a DOPA decarboxylase inhibitor, and    -   b. a pulsatile release component providing for a predetermined        lag time followed by a pulse release of said levodopa and said        DOPA decarboxylase inhibitor.

It is also an aspect to provide a pulsatile release pharmaceuticalcomposition comprising, separately or together,

-   -   a. a first pulsatile release component comprising levodopa, said        first pulsatile release component providing for a predetermined        lag time followed by a pulse release of levodopa, and    -   b. a second pulsatile release component comprising a DOPA        decarboxylase inhibitor, said second pulsatile release component        providing for a predetermined lag time followed by a pulse        release of said DOPA decarboxylase inhibitor,

wherein in one embodiment the lag time of said first pulsatile releasecomponent comprising levodopa is longer than the lag time of said secondpulsatile release component comprising a DOPA decarboxylase inhibitor.

In one embodiment said DOPA decarboxylase inhibitor is selected from thegroup consisting of carbidopa, benserazide, methyldopa and DFMD(α-Difluoromethyl-DOPA), or a pharmaceutically acceptable derivativethereof.

In one embodiment said pharmaceutical composition is a multiparticulatedosage form.

In one embodiment said pharmaceutical composition comprises, separatelyor together, one or more further active pharmaceutical ingredients.

In one embodiment said pharmaceutical composition is for use in thetreatment of morning akinesia in a patient with Parkinson's disease.

DESCRIPTION OF DRAWINGS

FIG. 1 : Pharmacokinetic profiles for levodopa products; A) standardimmediate release, B) standard controlled release, and C) proposeddelayed pulsatile product.

FIG. 2 : Release of Model Compound: Mini-tablets with 30% Sodium starchglycolate coated with ethylcellulose film (20-25% weight increase):Lag-time achieved with release of 50% from 3 to 5 h with 25% coating.Some variation in data (see Example 1).

FIG. 3A: Release of Model Compound: 30% Sodium starch glycolate coatedwith ethylcellulose film (10-25% weight increase); 10% PVA added as poreformer. Lag-time achieved with release of 65% from 3 to 5 h with 15%coating for 10% PVA.

FIG. 3B: Release of Model Compound: 30% Sodium starch glycolate coatedwith ethylcellulose film (10-25% weight increase); 20% PVA added as poreformer. Lag-time achieved with release of 70% from 3 to 5 h with 20%coating for 20% PVA. Less variation in data (see Examples 2 and 3).

FIG. 4A: Release of Model Compound: 30% Sodium starch glycolate coatedwith ethylcellulose film (10-25% weight increase); 10% HPMC added aspore former. Lag-time achieved with release of 50% from 3 to 5 h with15% coating for 10% HPMC. Increased film weight correlates with slowerrelease/less burst; and increased pore former correlates with higherburst release. Low variation in data (see Examples 4 and 5).

FIG. 4B: Release of Model Compound: 30% Sodium starch glycolate coatedwith ethylcellulose film (10-25% weight increase); 20% HPMC added aspore former. Lag-time achieved with release of 75% from 3 to 5 h with20% coating for 20% HPMC. Increased film weight correlates with slowerrelease/less burst; and increased pore former correlates with higherburst release. Low variation in data (see Examples 4 and 5).

FIG. 5 : Levodopa release: Mini-tablets with 30% Sodium starch glycolatecoated with ethylcellulose film (17.5-25% weight increase); 20% HPMCadded as pore former. Release from Levodopa mini-tablets is wellcontrolled (see Example 9).

FIG. 6 : Levodopa release: Mini-tablets with 30% Sodium starch glycolatecoated with ethylcellulose film (10-25% weight increase); 20% HPMC addedas pore former. Release from Levodopa mini-tablets is well controlled.Data from release of Model compound included to demonstrate similarrelease patterns (see Example 8).

FIG. 7 : Levodopa release: Mini-tablets with 10% Sodium starch glycolatecoated with ethylcellulose film (10-25% weight increase); 20% HPMC addedas pore former. Release from Levodopa mini-tablets with low level ofsuper disintregrant is not well controlled and display poor burstrelease (see Example 10).

FIG. 8 : Carbidopa release: Mini-tablets with 40% Sodium starchglycolate coated with ethylcellulose film (17.5-25% weight increase);20% HPMC added as pore former. Release from Carbidopa mini-tablets iswell controlled (see Example 17).

DETAILED DESCRIPTION

It is an aspect to provide a pharmaceutical composition that providesfor timed pulsatile release of levodopa and a DOPA decarboxylaseinhibitor such as carbidopa in the small intestine; preferably separatedin time whereby the DOPA decarboxylase inhibitor such as carbidopa ispulse released before levodopa. By ingesting such composition prior tosleep provides a means for treating morning akinesia in patients withe.g. Parkinson's disease.

It is recognized that gastric motility generally is somewhat delayed inpatients with Parkinson's disease, hence a lag time release of up to 5or 6 hours while the composition still is in the small intestine isfeasible. Delivering a full dose of levodopa in a burst in the lowerpart of the small intestine is expected to improve the absorption oflevodopa. Bioabsorption in this region is not possible with the currentmarketed levodopa products, and therefore the new principle provides aunique new opportunity for having over-night levodopa coverage for theParkinson patient.

L-DOPA or levodopa (L-3,4-dihydroxyphenylalanine) in humans issynthesized from the amino acid L-tyrosine. L-DOPA is the precursor tothe neurotransmitters dopamine, noradrenaline and adrenaline andmediates neurotrophic factor release by the brain and CNS. L-DOPA issold as a psychoactive drug with the INN levodopa; trade names includeSinemet, Pharmacopa, Atamet, Stalevo, Madopar, and Prolopa. It is usedin the clinical treatment of Parkinson's disease and dopamine-responsivedystonia.

L-DOPA crosses the blood-brain barrier where it is converted intodopamine by aromatic L-amino acid decarboxylase (DOPA decarboxylase).Since L-DOPA is also converted into dopamine from within the peripheralnervous system, causing excessive peripheral dopamine signaling andadverse effects, it is standard clinical practice to co-administer aperipheral DOPA decarboxylase inhibitor (DDCI). Combined therapypotentiates the central effects of L-DOPA by decreasing thedose-dependency 4-5 fold.

DOPA decarboxylase inhibitors includes carbidopa, benserazide,methyldopa and DFMD (α-Difluoromethyl-DOPA).

Medicines containing carbidopa, either alone or in combination withL-DOPA, are branded as Lodosyn (Aton Pharma), Sinemet (Merck Sharp &Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Stalevo(Orion Corporation), parcopa, or with a benserazide (combinationmedicines are branded Madopar or Prolope).

Medicines containing benserazide either alone or in combination withL-DOPA are branded as Madopar, Prolopa, Modopar, Madopark, Neodopasol,EC-Doparyl, etc. Medicines containing methyldopa are branded as Aldomet,Aldoril, Dopamet, Dopegyt, etc.

Pulsatile drug delivery is defined as the rapid and transient release ofcertain amount of molecules within a short time period immediately aftera predetermined off-released period, i.e., lag time.

Pulsatile drug delivery systems (PDDS) deliver the drug at the righttime, at the right site of action and in the right amount, and the drugis released rapidly and completely as a pulse (or burst) after a lagtime. These products follow the sigmoid release profile characterized bya time period. Such a release pattern is known as pulsatile release.These systems are beneficial for the drug with chrono-pharmacologicalbehavior, where nocturnal dosing is required, and for drugs that showfirst pass effect. Potential disadvantages include low drug loadingcapacity and multiple manufacturing steps.

Lag time is defined as the time between when a dosage form is placedinto an aqueous environment and the time at which the activepharmaceutical ingredient begins to get released from the dosage form.

Pulsatile drug delivery systems may be broadly classified in threecategories:

-   -   1) Time controlled pulsatile release systems (delivery systems        containing erodible coating layer)        -   a. Bulk-eroding systems. Bulk erosion means that the ingress            of water is faster than the rate of degradation. In this            case, degradation take places throughout the polymer sample            and proceeded until a critical molecular weight is reached.            At this point, degradation products become smaller enough to            be solubilised and the structure starts to become            significantly more porous and hydrated. Hence there is a            time lag before the drug can be released, corresponding to            the time required for critical molecular weight to be            reached.        -   b. Surface-eroding systems. In this type of system, the            reservoir device is coated with soluble or erodible layer,            which dissolves with time and releases the drug after a            specified lag period. When this system comes in contact with            aqueous medium the coat emulsifies or erodes after the            lag-time. It is independent of the gastrointestinal            motility, pH, enzyme and gastric residence. The lag time and            onset of action are controlled by thickness and the            viscosity grade of the polymer used. Examples include            delivery systems with rupturable coating layer and            capsule-shaped system with release controlling plug.            -   a. The coating can be spray coated (e.g. rupture film                coatings or erodible film coatings) or compression                coated.    -   2) Stimuli-induced pulsatile release system. Stimuli based drug        delivery systems release the drug in response to stimuli that        are induced by the biological environment, such as changes in        temperature (thermo-responsive pulsatile release) and chemical        stimuli such as pH, enzymes or other chemicals (chemical        stimuli-induced pulsatile release).    -   3) Externally regulated pulsatile release system. These include        electrically responsive delivery systems (prepared from        polyelectrolytes and thus pH-responsive as well as electro        responsive); ultrasonically stimulated; and magnetically induced        pulsatile release.

Provided herewith is a pulsatile drug delivery system providing for thetimed pulsatile release of levodopa and a DOPA decarboxylase inhibitor.In one embodiment the pulsatile drug delivery system is a pharmaceuticalcomposition for timed pulsatile release of levodopa and a DOPAdecarboxylase inhibitor.

A pharmaceutical composition and a pulsatile release pharmaceuticalcomposition may be used interchangeably herein.

In one aspect there is provided a pulsatile release pharmaceuticalcomposition comprising

-   -   i) levodopa and a DOPA decarboxylase inhibitor, and    -   ii) a pulsatile release component providing for a predetermined        lag time followed by a pulse release of said levodopa and said        DOPA decarboxylase inhibitor.

In one aspect there is provided a pharmaceutical composition comprising,separately or together,

-   -   i) a first pulsatile release component comprising levodopa, said        first pulsatile release component providing for a predetermined        lag time followed by a pulse release of levodopa, and    -   ii) a second pulsatile release component comprising a DOPA        decarboxylase inhibitor, said second pulsatile release component        providing for a predetermined lag time followed by a pulse        release of said DOPA decarboxylase inhibitor.

In one embodiment the lag time of said first pulsatile release componentcomprising levodopa is longer than the lag time of said second pulsatilerelease component comprising a DOPA decarboxylase inhibitor.

In one aspect there is provided a pharmaceutical composition comprising,separately or together,

-   -   i) a first pulsatile release component comprising levodopa, said        first pulsatile release component providing for a predetermined        lag time followed by a pulse release of levodopa, and    -   ii) a second pulsatile release component comprising a DOPA        decarboxylase inhibitor, said second pulsatile release component        providing for a predetermined lag time followed by a pulse        release of said DOPA decarboxylase inhibitor,

wherein the lag time of said first pulsatile release componentcomprising levodopa is longer than the lag time of said second pulsatilerelease component comprising a DOPA decarboxylase inhibitor.

In one embodiment the DOPA decarboxylase inhibitor is selected from thegroup consisting of carbidopa, benserazide, methyldopa and DFMD(α-Difluoromethyl-DOPA), or a pharmaceutically acceptable derivativethereof.

In one embodiment the DOPA decarboxylase inhibitor is carbidopa, orpharmaceutically acceptable derivative thereof.

In one embodiment the term levodopa comprises also pharmaceuticallyacceptable derivatives of levodopa.

In one embodiment the term levodopa comprises levodopa pro-drugs. In oneembodiment the term levodopa comprises the levodopa pro-drug levodopamethyl ester. In one embodiment the term levodopa comprises the levodopapro-drug XP21279.

In one embodiment the term levodopa comprises also modified levodopa. Inone embodiment the term levodopa comprises also deuterated levodopa(deuterium substituted levodopa).

The term “pharmaceutically acceptable derivative” in present contextincludes pharmaceutically acceptable salts, which indicate a salt whichis not harmful to the patient. Such salts include pharmaceuticallyacceptable basic or acid addition salts as well as pharmaceuticallyacceptable metal salts, ammonium salts and alkylated ammonium salts. Apharmaceutically acceptable derivative further includes esters andprodrugs, or other precursors of a compound which may be biologicallymetabolized into the active compound, or crystal forms of a compound.

In one embodiment the pharmaceutical composition is a time controlledpulsatile release system, including bulk-eroding systems andsurface-eroding systems.

In one embodiment the pharmaceutical composition is a pharmaceuticaldosage form. In one embodiment the pharmaceutical dosage form is amultiparticulate dosage form (multiple unit dosage forms).

Multiparticulates or multiple unit dosage forms are the discrete, small,repetitive units of drug particles which may or possess similar drugrelease pattern. They can be tailored for pulsatile drug release.

In one embodiment the pharmaceutical dosage form is a multiparticulatedosage form comprising a plurality of particles, each particle providingfor timed pulsatile release of levodopa and/or a DOPA decarboxylaseinhibitor.

In one embodiment the pharmaceutical dosage form is a multiparticulatedosage form comprising, separately or together, two dosage forms:

-   -   i) a first dosage form providing for a predetermined lag time        followed by a pulse release of levodopa, and    -   ii) a second dosage form providing for a predetermined lag time        followed by a pulse release of a DOPA decarboxylase inhibitor.

In one embodiment the pharmaceutical dosage form is a multiparticulatedosage form comprising, separately or together, two dosage forms:

-   -   i) a first dosage form providing for a predetermined lag time        followed by a pulse release of levodopa, and    -   ii) a second dosage form providing for a predetermined lag time        followed by a pulse release of a DOPA decarboxylase inhibitor,

wherein the lag time of said first dosage form comprising levodopa islonger than the lag time of said second dosage form comprising a DOPAdecarboxylase inhibitor.

In one embodiment the multiparticulate dosage form is packaged in acapsule, a pouch a sachet or a stick pack. In one embodiment the firstdosage form comprising levodopa and the second dosage form comprising aDOPA decarboxylase inhibitor are packaged in a capsule, a pouch, asachet or a stick pack. In one embodiment the capsule is a hard-shelledcapsule, such as hard-capsule gelatin.

In one embodiment the multiparticulate dosage form

-   -   i) comprises 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8        to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15,        15 to 16, 16 to 17, 17 to 18, 18 to 19, 19 to 20, 20 to 21, 21        to 22, 22 to 23, 23 to 24, 24 to 25, 25 to 26, 26 to 27, 27 to        28, 28 to 29, 29 to 30, 30 to 35, 35 to 40, 40 to 45, 45 to 50,        50 to 55, 55 to 60, 60 to 65, 65 to 70, 70 to 75, 75 to 80, 80        to 85, 85 to 90, 90 to 95, 95 to 100, 100 to 110, 110 to 120,        120 to 130, 130 to 140, 140 to 150, 150 to 160, 160 to 170, 170        to 180, 180 to 190, 190 to 200 first dosage forms comprising        levodopa; and    -   ii) comprises 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8        to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15,        15 to 16, 16 to 17, 17 to 18, 18 to 19, 19 to 20, 20 to 21, 21        to 22, 22 to 23, 23 to 24, 24 to 25, 25 to 26, 26 to 27, 27 to        28, 28 to 29, 29 to 30, 30 to 35, 35 to 40, 40 to 45, 45 to 50,        50 to 55, 55 to 60, 60 to 65, 65 to 70, 70 to 75, 75 to 80, 80        to 85, 85 to 90, 90 to 95, 95 to 100, 100 to 110, 110 to 120,        120 to 130, 130 to 140, 140 to 150, 150 to 160, 160 to 170, 170        to 180, 180 to 190, 190 to 200 second dosage forms comprising a        DOPA decarboxylase inhibitor.

The number of dosage forms in the multiparticulate dosage form isdetermined by factors such as dosage of active pharmaceutical ingredientand size of dosage form.

In one embodiment the pharmaceutical dosage form; such as the first andthe second dosage form, is an oral solid dosage form. In one embodimentthe oral solid dosage form is selected from the group consisting of atablet, a mini-tablet, a micro-tablet, a sphere, a pellet, a granule anda capsule.

In one embodiment the oral solid dosage form comprises a coating. In oneembodiment the oral solid dosage form comprises a core with a coating.In one embodiment the core comprises the active pharmaceuticalingredient. In one embodiment the coating does not contain the activepharmaceutical ingredient.

In one embodiment the oral solid dosage form is selected from the groupconsisting of a coated tablet, a coated mini-tablet, a coatedmicro-tablet, a coated sphere, a coated pellet, a coated granule and acoated capsule.

In one embodiment the oral solid dosage form comprise a swellable andsoluble core.

In one embodiment the coating is a film coating.

In one embodiment the coating is a semi-permeable coating, such as asemi-permeable insoluble film coating. Upon swelling of the core theactive pharmaceutical ingredient is released through the semi-permeablefilm coating.

In one embodiment the coating is an insoluble coating.

In one embodiment the coating is a rupturable coating.

In one embodiment the coating is a rupturable insoluble coating. Uponswelling of the core component the outer coating ruptures and burstreleases the contents.

In one embodiment the coating is a soluble or erodible coating.

In one embodiment the oral solid dosage form comprises a soluble corecoated with an insoluble film, such as an insoluble semipermeable film.

In one embodiment the pharmaceutical dosage form is a coatedmini-tablet. In one embodiment the pharmaceutical dosage form is atablet, such as a coated tablet. In one embodiment the pharmaceuticaldosage form is a tablet comprising coated mini-tablets compressed into atablet.

In one embodiment the coating is spray coated. In one embodiment thecoating is compression coated.

In one embodiment the outer coating comprises a film-forming polymer. Inone embodiment the outer coating comprises a water-insoluble polymer. Inone embodiment the outer coating further comprises a pore-former, suchas a hydrophilic pore former.

Mini-tablets are tablets with a diameter 3 mm, and represent a new trendin solid dosage form design, which overcomes some therapeutic obstaclessuch as impaired swallowing and polypharmacy therapy, and also offeringsome therapeutic benefits such as dose flexibility and combined releasepatterns.

In one embodiment a mini-tablet is a tablet with a diameter less than orequal to (≤)3 mm, such as ≤2.5 mm, for example ≤2 mm, such as ≤1.5 mm,for example ≤1 mm. In one embodiment a mini-tablet is a tablet with adiameter of 1 to 1.5 mm, such as 1.5 to 2 mm, for example 2 to 2.5 mm,such as 2.5 to 3 mm. In one embodiment a mini-tablet is a tablet with adiameter of approximately 2 mm.

In one embodiment the pharmaceutical composition provides for a sigmoidrelease profile of levodopa and of a DOPA decarboxylase inhibitor,preferably shifted in time wherein the lag time of a first pulsatilerelease of levodopa is longer than the lag time of the second pulsatilerelease of a DOPA decarboxylase inhibitor.

The lag time for the pulsatile release component is adjusted to releasesaid levodopa and said DOPA decarboxylase inhibitor in the smallintestine, such as the lower part of the small intestine.

In one embodiment the lag time for the pulsatile release componentcomprising levodopa and DOPA decarboxylase inhibitor is between 2 to 8hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours,such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours.

The lag time for the first pulsatile release component comprisinglevodopa, and for the second pulsatile release component comprising aDOPA decarboxylase inhibitor is preferably adjusted to release theactive pharmaceutical ingredients in the small intestine, such as thelower part of the small intestine. Preferably, the DOPA decarboxylaseinhibitor is released before the levodopa is released in the smallintestine, such as the lower part of the small intestine.

In one embodiment the lag time for the first pulsatile release componentcomprising levodopa is between 2 to 8 hours; such as 2 to 3 hours, suchas 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6to 7 hours, such as 7 to 8 hours.

In one embodiment thee lag time for the first pulsatile releasecomponent comprising levodopa is 3 to 6 hours, such as 4 to 6 hours,such as 3 to 5 hours.

In one embodiment the lag time for the first pulsatile release componentcomprising levodopa is at least 2 hours, such as at least 3 hours, suchas at least 4 hours.

In one embodiment the lag time for the second pulsatile releasecomponent comprising a DOPA decarboxylase inhibitor is between 2 to 8hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours,such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours.

In one embodiment thee lag time for the second pulsatile releasecomponent comprising a DOPA decarboxylase inhibitor is 3 to 6 hours,such as 4 to 6 hours, such as 3 to 5 hours.

In one embodiment the lag time for the second pulsatile releasecomponent comprising a DOPA decarboxylase inhibitor is at least 2 hours,such as at least 3 hours, such as at least 4 hours.

In one embodiment the lag time of the first dosage form comprisinglevodopa and the second dosage form comprising a DOPA decarboxylaseinhibitor is shifted in time, whereby the lag time of the first dosageform comprising levodopa is longest.

In one embodiment the lag time of the first dosage form comprisinglevodopa is longer than the lag time of the second dosage formcomprising a DOPA decarboxylase inhibitor, such that the DOPAdecarboxylase inhibitor is release before levodopa is released.

In one embodiment the lag time of the first dosage form comprisinglevodopa is 5 minutes to 90 minutes longer than the lag time of thesecond dosage form comprising a DOPA decarboxylase inhibitor; such as 5to 10 minutes, such as 10 to 15 minutes, such as 15 to 20 minutes, suchas 20 to 25 minutes, such as 25 to 30 minutes, such as 30 to 35 minutes,such as 35 to 40 minutes, such as 40 to 45 minutes, such as 45 to 50minutes, such as 50 to 55 minutes, such as 55 to 60 minutes, such as 60to 65 minutes, such as 65 to 70 minutes, such as 70 to 75 minutes, suchas 75 to 80 minutes, such as 80 to 85 minutes, such as 85 to 90 minuteslonger than the lag time of the second dosage form comprising a DOPAdecarboxylase inhibitor.

In one embodiment the lag time of the first dosage form comprisinglevodopa is 90 minutes to 240 minutes longer than the lag time of thesecond dosage form comprising a DOPA decarboxylase inhibitor; such as 90to 100 minutes, such as 100 to 110 minutes, such as 110 to 120 minutes,such as 120 to 130 minutes, such as 130 to 140 minutes, such as 140 to150 minutes, such as 150 to 160 minutes, such as 160 to 170 minutes,such as 170 to 180 minutes, such as 180 to 200 minutes, such as 200 to220 minutes, such as 220 to 240 minutes longer than the lag time of thesecond dosage form comprising a DOPA decarboxylase inhibitor.

In one embodiment the lag time of the first dosage form comprisinglevodopa is at least 5 minutes longer than the lag time of the seconddosage form comprising a DOPA decarboxylase inhibitor, such as at least10 minutes longer, such as at least 15 minutes longer, such as at least20 minutes longer, such as at least 25 minutes longer, such as at least30 minutes longer, such as at least 35 minutes, such as at least 40minutes longer, such as at least 45 minutes, such as at least 50 minuteslonger, such as at least 55 minutes, such as at least 60 minutes longerthan the lag time of the second dosage form comprising a DOPAdecarboxylase inhibitor.

In one embodiment the lag time of the first dosage form comprisinglevodopa is approximately 10 minutes longer, such as approximately 15minutes longer, such as approximately 20 minutes longer, such asapproximately 25 minutes longer, such as approximately 30 minuteslonger, such as approximately 35 minutes, such as approximately 40minutes longer, such as approximately 45 minutes, such as approximately50 minutes longer, such as approximately 55 minutes, such asapproximately 60 minutes longer than the lag time of the second dosageform comprising a DOPA decarboxylase inhibitor.

After the lag time the active pharmaceutical ingredient is released fromthe pharmaceutical composition or dosage form.

In one embodiment the first dosage form comprising levodopa is releasedbefore the second dosage form comprising a DOPA decarboxylase inhibitor.

In one embodiment the first dosage form comprising levodopa is released5 to 10 minutes before, such as 10 to 15 minutes, such as 15 to 20minutes, such as 20 to 25 minutes, such as 25 to 30 minutes, such as 30to 35 minutes, such as 35 to 40 minutes, such as 40 to 45 minutes, suchas 45 to 50 minutes, such as 50 to 55 minutes, such as 55 to 60 minutes,such as 60 to 65 minutes, such as 65 to 70 minutes, such as 70 to 75minutes, such as 75 to 80 minutes, such as 80 to 85 minutes, such as 85to 90 minutes before release of the second dosage form comprising a DOPAdecarboxylase inhibitor.

In one embodiment the pharmaceutical composition releases 70 to 100% ofthe drug load measured at 2 to 5 hours after the lag phase, i.e.releases 70 to 100% of the levodopa and/or the DOPA decarboxylaseinhibitor measured at 2 to 5 hours.

In one embodiment the pharmaceutical composition releases 70 to 100% ofthe drug load measured at 2 to 5 hours, such as releases 70 to 75%, suchas 75 to 80%, such as 80 to 85%, such as 85 to 90%, such as 90 to 95%,such as 95 to 100% of the drug load measured at 2 to 5 hours.

In one embodiment the pharmaceutical composition releases up to 100% ofthe drug load within 2 hours after the lag phase. In one embodiment thepharmaceutical composition releases 70%, such as 80%, such as 90%, suchas 100% of the drug load within 2 hours after the lag phase. In oneembodiment the pharmaceutical composition releases 70%, such as 80%,such as 90%, such as 100% of the drug load within 2 to 5 hours after thelag phase, such as within 2 hours, such as within 3 hours, such aswithin 4 hours, such as within 5 hours.

Coated Tablets

In one embodiment the pharmaceutical dosage form comprises one or morecoated tablets comprising levodopa and a DOPA decarboxylase inhibitorproviding for a predetermined lag time followed by a pulse release ofsaid levodopa and said DOPA decarboxylase inhibitor.

In one embodiment the pharmaceutical dosage form is a multiparticulatedosage form comprising, separately or together,

-   -   i) coated tablets providing for a predetermined lag time        followed by a pulse release of levodopa, and    -   ii) coated tablets providing for a predetermined lag time        followed by a pulse release of a DOPA decarboxylase inhibitor.

In one embodiment the lag time of said coated tablets comprisinglevodopa is longer than the lag time of said coated tablets comprising aDOPA decarboxylase inhibitor.

In one embodiment the coated tablets comprise a tablet core comprisingthe active pharmaceutical ingredient and an outer coating.

Coated tablets comprise both coated tablets and coated mini-tablets. Inone embodiment the coated tablets are coated tablets. In one embodimentthe coated tablets are coated mini-tablets.

In one embodiment the coated tablets comprise a swellable and solublemini-tablet core.

In one embodiment the coated tablets comprise a semi-permeable filmcoating. Upon swelling of the core the active pharmaceutical ingredientis released through the semipermeable film.

In one embodiment the coated tablets are coated mini-tablets comprisinga semi-permeable film coating. Upon swelling of the mini-tablet core theactive pharmaceutical ingredient is released through the semipermeablefilm.

In one embodiment the coated tablets comprise a rupturable insolublecoating. Upon swelling of the core component the outer coating rupturesand burst releases the contents.

In one embodiment coated mini-tablets comprising levodopa comprise aswellable and soluble mini-tablet core comprising levodopa and an outersemipermeable film coating.

In one embodiment coated mini-tablets comprising a DOPA decarboxylaseinhibitor comprise a swellable and soluble mini-tablet core comprising aDOPA decarboxylase inhibitor and an outer semipermeable film coating.

In one embodiment coated tablets comprising levodopa comprise aswellable and soluble tablet core comprising levodopa and a rupturableinsoluble coating.

In one embodiment coated tablets comprising a DOPA decarboxylaseinhibitor comprise a swellable and soluble tablet core comprising a DOPAdecarboxylase inhibitor and a rupturable insoluble coating.

In one embodiment the tablet core comprising levodopa comprises orconsists of:

-   -   levodopa    -   a superdisintegrant,    -   one or more excipients, and    -   optionally an anti-adherent.

In one embodiment the tablet core comprises 25 to 75% w/w levodopa, suchas 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%,such as 45 to 50%, such as 50 to 55%, such as 60 to 65%, such as 65 to70%, such as 70 to 75% w/w levodopa.

In one embodiment the mini-tablet core comprises 1 to 5 mg levodopa,such as 1 to 1.25 mg, such as 1.25 to 1.5 mg, such as 1.5 to 1.75 mg,such as 1.75 to 2 mg, such as 2 to 2.25 mg, such as 2.25 to 2.5 mg, suchas 2.5 to 2.75 mg, such as 2.75 to 3 mg, such as 3 to 3.25 mg, such as3.25 to 3.5 mg, such as 3.5 to 3.75 mg, such as 3.75 to 4 mg, such as 4to 4.25 mg, such as 4.25 to 4.5 mg, such as 4.5 to 4.75 mg, such as 4.75to 5 mg levodopa. In one embodiment the mini-tablet core comprises 2.5to 3.5 mg levodopa. In one embodiment the mini-tablet core comprises atleast 2, such as at least 2.5 mg levodopa.

In one embodiment the tablet core comprising a DOPA decarboxylaseinhibitor comprises or consists of:

-   -   a DOPA decarboxylase inhibitor,    -   a superdisintegrant,    -   one or more excipients, and    -   optionally an anti-adherent.

In one embodiment the tablet core comprises 25 to 75% w/w DOPAdecarboxylase inhibitor, such as 25 to 30%, such as 30 to 35%, such as35 to 40%, such as 40 to 45%, such as 45 to 50%, such as 50 to 55%, suchas 60 to 65%, such as 65 to 70%, such as 70 to 75% w/w DOPAdecarboxylase inhibitor.

A superdisintegrant is an agent used in pharmaceutical preparation oftablets, which causes them to disintegrate and release their medicinalsubstances on contact with moisture.

In one embodiment the tablet core comprises 15 to 50% w/wsuperdisintegrant, such as 15 to 20%, such as 20 to 25%, such as 25 to30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45to 50% w/w superdisintegrant. In one embodiment the tablet corecomprises at least 20% w/w superdisintegrant, such as at least 25%, suchas at least 30% w/w superdisintegrant. In one embodiment the tablet corecomprises at approx. 30% w/w superdisintegrant.

In one embodiment the superdisintegrant is selected from Crosslinkedstarch, Crosslinked Cellulose, Crosslinked PVP (polyvinylpyrrolidone),Crosslinked alginic acid, Soy polysaccharides, Calcium silicate, Gellangum and Xanthan gum.

In one embodiment the tablet core comprises one or moresuperdisintegrants selected from the group consisting of sodium starchglycolate (sodium carboxymethyl starch), croscarmellose sodium,crospovidone, crospovidone XL, crospovidone CL and low-substitutedhydroxypropylcellulose (L-HPC). In one embodiment the superdisintegrantis sodium starch glycolate.

An excipient is a pharmacologically inactive (or chemically inactive)substance formulated with the active pharmaceutical ingredient of amedication. Excipients are commonly used to bulk up formulations thatcontain active pharmaceutical ingredients (thus often referred to as“bulking agents,” “fillers,” or “diluents”) to allow convenient andaccurate dispensation of a drug substance when producing a dosage form.

In one embodiment the tablet core comprises 10 to 50% w/w excipients,such as 10 to 15%, such as 15 to 20%, such as 20 to 25%, such as 25 to30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45to 50% w/w excipients.

In one embodiment said excipients act as binder, filler, solid carrier,diluent, flavouring agent, solubilizer, lubricant, glidant, suspendingagent, preservative, anti-adherent, wetting agent, disintegrating agentor sorbent or combinations thereof.

In one embodiment the tablet core comprises one or more fillers, such asa filler selected from the group consisting of calcium carbonate,calcium phosphates, calcium sulfate, cellulose, cellulose acetate,compressible sugar, dextrate, dextrin, dextrose, ethylcellulose,fructose, isomalt, lactitol, lactose, mannitol, magnesium carbonate,magnesium oxide, maltodextrin, microcrystalline cellulose (MCC),polydextrose, sodium alginate, sorbitol, talc and xylitol.

In one embodiment the tablet core comprises one or more binders, such asa binder selected from the group consisting of acacia, alginic acid,carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetatephthalate, chitosan, copovidone, dextrate, dextrin, dextrose,ethylcellulose, gelatin, guar gum, hydroyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylstarch, hydroxypropylmethylcellulose (HPMC or hypromellose),methylcellulose, microcrystalline cellulose (MCC), poloxamer,polydextrose, polyethylene oxide, povidone, sodium alginate, sucrose,starch, pregelatinized starch and maltodextrin.

In one embodiment the tablet core comprises one or more wet binders. Inone embodiment the mini-tablet core comprises one or more wet bindersselected from the group consisting of pregelatinized starch, HPMC,methylcellulose and gelatin.

In one embodiment the tablet core comprises 5 to 25% w/w binder, such as5 to 7.5%, such as 7.5 to 10%, such as 10 to 12.5%, such as 12.5 to 15%,such as 15 to 17.5%, such as 17.5 to 20%, such as 20 to 22.5%, such as22.5 to 25% w/w binder.

In one embodiment the tablet core comprises 1 to 20% w/w wet binder,such as 1 to 2.5%, such as 2.5 to 5%, such as 5 to 7.5%, such as 7.5 to10%, such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, suchas 17.5 to 20% w/w wet binder.

In one embodiment the mini-tablet core comprises microcrystallinecellulose (MCC) and pregelatinized starch.

In one embodiment the tablet core comprises 5 to 25% w/wmicrocrystalline cellulose, such as 5 to 7.5%, such as 7.5 to 10%, suchas 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as 17.5to 20%, such as 20 to 22.5%, such as 22.5 to 25% w/w microcrystallinecellulose. In one embodiment the mini-tablet core comprises 10 to 20%w/w microcrystalline cellulose.

In one embodiment the tablet core comprises 1 to 20% w/w pregelatinizedstarch, such as 1 to 2.5%, such as 2.5 to 5%, such as 5 to 7.5%, such as7.5 to 10%, such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to17.5%, such as 17.5 to 20% w/w pregelatinized starch. In one embodimentthe mini-tablet core comprises 5 to 15% w/w such as 5 to 10% w/wpregelatinized starch.

In one embodiment the tablet core comprises an anti-adherent, such ascomprises 0.25 to 0.50% w/w anti-adherent, such as 0.50 to 0.75%, suchas 0.75 to 1.0%, such as 1.0 to 1.25, such as 1.25 to 1.50, such as 1.50to 1.75%, such as 1.75 to 2.0% w/w anti-adherent.

In one embodiment the anti-adherent is selected from the groupconsisting of magnesium stearate, calcium stearate, zinc stearate,glyceryl monostearate, hydrogenated castor oil, hydrogenated vegetableoil, medium chain glycerides, palmitic acid, poloxamers, polyethyleneglycols, stearic acid and talc. In one embodiment the anti-adherent ismagnesium stearate.

In one embodiment the tablet core comprising levodopa comprises orconsists of:

-   -   25 to 75% w/w levodopa; such as 25 to 30%, such as 30 to 35%,        such as 35 to 40%, such as 40 to 45%, such as 45 to 50%, such as        50 to 55%, such as 60 to 65%, such as 65 to 70%, such as 70 to        75% w/w levodopa,    -   15 to 50% w/w superdisintegrant; such as 15 to 20%, such as 20        to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%,        such as 40 to 45%, such as 45 to 50% w/w superdisintegrant,    -   10 to 50% w/w excipients; such as 10 to 15%, such as 15 to 20%,        such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as        35 to 40%, such as 40 to 45%, such as 45 to 50% w/w excipients,        and    -   0 to 2% w/w anti-adherent; such as 0.25 to 0.50% w/w        anti-adherent, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such        as 1.0 to 1.25, such as 1.25 to 1.50, such as 1.50 to 1.75%,        such as 1.75 to 2.0% w/w anti-adherent.

In one embodiment the tablet core comprising levodopa comprises orconsists of:

-   -   40 to 60% w/w levodopa,    -   20 to 40% w/w superdisintegrant,    -   10 to 30% w/w excipients, and    -   0.5 to 1.5% w/w anti-adherent.

In one embodiment the tablet core comprising levodopa comprises orconsists of:

-   -   40 to 60% w/w, such as 45 to 55% w/w levodopa,    -   20 to 40% w/w, such as 25 to 35% w/w sodium starch glycolate,    -   5 to 25% w/w, such as 10 to 20% w/w microcrystalline cellulose,    -   1 to 20% w/w, such as 5 to 10% w/w pregelatinized starch, and    -   0.5 to 1.5% w/w, such as 1% w/w Mg stearate.

In one embodiment the tablet core comprising DOPA decarboxylaseinhibitor comprises or consists of:

-   -   25 to 75% w/w DOPA decarboxylase inhibitor; such as 25 to 30%,        such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as        45 to 50%, such as 50 to 55%, such as 60 to 65%, such as 65 to        70%, such as 70 to 75% w/w DOPA decarboxylase inhibitor,    -   15 to 50% w/w superdisintegrant; such as 15 to 20%, such as 20        to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%,        such as 40 to 45%, such as 45 to 50% w/w superdisintegrant,    -   10 to 50% w/w excipients; such as 10 to 15%, such as 15 to 20%,        such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as        35 to 40%, such as 40 to 45%, such as 45 to 50% w/w excipients,        and    -   0 to 2% w/w anti-adherent; such as 0.25 to 0.50% w/w        anti-adherent, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such        as 1.0 to 1.25, such as 1.25 to 1.50, such as 1.50 to 1.75%,        such as 1.75 to 2.0% w/w anti-adherent.

In one embodiment the tablet core comprises carbidopa.

In one embodiment the coated tablet is manufactured by granulation,compression and subsequent film coating.

In one embodiment coated mini-tablets are compressed to form a tablet.In one embodiment coated mini-tablets are packaged in a capsule, a poucha sachet or a stick pack.

Coating

It is envisioned that the outer coating is applied to increase theweight of the tablet to a certain extent, whereby release of substancesis delayed. Weight increase or weight gain as defined herein isincreased relative to the tablet core weight.

In one embodiment an outer coating is applied to increase the weight ofa mini-tablet core by 10 to 40% w/w, such as 10 to 12.5%, such as 12.5to 15%, such as 15 to 17.5%, such as 17.5 to 20%, such as 20 to 22.5%,such as 22.5 to 25%, such as 25 to 27.5%, such as 27.5 to 30%, such as30 to 32.5%, such as 32.5 to 35%, such as 35 to 37.5%, such as 37.5 to40% w/w. In one embodiment this applies to mini-tablet cores comprisinglevodopa and mini-tablet cores comprising a DOPA decarboxylaseinhibitor.

In one embodiment an outer coating is applied to increase the weight ofa mini-tablet core by 17.5% to 25% w/w, such as 20 to 25% w/w.

In one embodiment an outer coating is applied to increase the weight ofa mini-tablet core by at least 15% w/w, such as at least 17.5%, such asat least 20%, such as at least 22.5%, such as at least 25% w/w.

In one embodiment the outer coating is applied to increase the weight ofa mini-tablet core by approximately 15% w/w, such as approximately17.5%, such as approximately 20%, such as approximately 22.5%, such asapproximately 25%, such as approximately 27.5%, such as approximately30% w/w.

In one embodiment an outer coating is applied to increase the weight ofa tablet core (not mini-tablet) by 1 to 20% w/w, such as 1 to 2.5%, suchas 2.5 to 5%, such as 5 to 7.5%, such as 7.5 to 10%, such as 10 to12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as 17.5 to 20%w/w. In one embodiment this applies to tablet cores comprising levodopaand tablet cores comprising a DOPA decarboxylase inhibitor.

In one embodiment the outer coating is applied to the tablet corecomprising levodopa to achieve the desired lag time defined hereinelsewhere.

In one embodiment the outer coating is applied to the tablet corecomprising a DOPA decarboxylase inhibitor to achieve the desired lagtime defined herein elsewhere.

In one embodiment the weight increase of the outer coating of the tabletcore comprising levodopa, and the weight increase of the outer coatingof the tablet core comprising a DOPA decarboxylase inhibitor, areadjusted in order to release levodopa before the DOPA decarboxylaseinhibitor, as specified herein.

In one embodiment the weight increase of the outer coating of the tabletcore comprising levodopa is higher than and the weight increase of theouter coating of the tablet core comprising a DOPA decarboxylaseinhibitor.

In one embodiment the weight increase of the outer coating of the tabletcore comprising levodopa is 1 to 25 percentage point higher than and theweight increase of the outer coating of the tablet core comprising aDOPA decarboxylase inhibitor, such as 1 to 2 percentage point, such as 2to 3 percentage point, such as 3 to 4 percentage point, such as 4 to 5percentage point, such as 5 to 6 percentage point, such as 6 to 7percentage point, such as 7 to 8 percentage point, such as 8 to 9percentage point, such as 9 to 10 percentage point, such as 10 to 11percentage point, such as 11 to 12 percentage point, such as 12 to 13percentage point, such as 13 to 14 percentage point, such as 14 to 15percentage point higher, such as 15 to 16 percentage point, such as 16to 17 percentage point, such as 17 to 18 percentage point, such as 18 to19 percentage point, such as 19 to 20 percentage point, such as 20 to 21percentage point, such as 21 to 22 percentage point, such as 22 to 23percentage point, such as 23 to 24 percentage point, such as 24 to 25percentage point higher.

In one embodiment the coating is an insoluble and rupturable film.

In one embodiment the coating is an insoluble and semipermeable film.

In one embodiment the coating is a semipermeable film.

In one embodiment the coating comprises a film-forming polymer.

In one embodiment the coating comprises a water-insoluble polymer.

In one embodiment the coating comprises one or more of ethylcellulose,hydroxypropyl cellulose, cellulose acetate, acrylic polymers, entericpolymers, hypromellose acetate succinate, shellac, vax andethylcellulose dispersions.

In one embodiment the coating comprises ethylcellulose.

In one embodiment the coating further comprises a pore-former, such as ahydrophilic pore former. In one embodiment the pore-former is selectedfrom the group consisting of polyvinyl alcohol (PVA), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyethyleneglycol (PEG).

In one embodiment the coating comprises a water-insoluble polymer and ahydrophilic pore former.

In one embodiment the coating comprises ethylcellulose and apore-former, such as a pore-former selected from PVA, HPMC, PVP and PEG.In one embodiment the outer coating comprises ethylcellulose and PVA. Inone embodiment the outer coating comprises ethylcellulose and HPMC.

In one embodiment the coating comprises 5 to 40% w/w pore-former, suchas 5 to 10% w/w, such as 10 to 15% w/w, such as 15 to 20% w/w, such as20 to 25% w/w, such as 25 to 30% w/w, such as 30 to 35% w/w, such as 35to 40% w/w pore-former. In one embodiment the outer coating comprises 10to 30%, such as 15 to 25% w/w pore-former.

In one embodiment the ratio in the coating of the film-forming polymer(or water-insoluble polymer) and hydrophilic pore-former is approx.10/90, 15/85, 20/80, 25/75 or 30/70.

In one embodiment the coating comprises approx. 80% w/w ethylcelluloseand approx. 20% w/w HPMC. In one embodiment the outer coating comprisesapprox. 80% w/w ethylcellulose and approx. 20% w/w PVA.

Administration and Dosage

The pharmaceutical composition disclosed herein is preferablyadministered to individuals in need of treatment in pharmaceuticallyeffective doses. A therapeutically effective amount of a compound oractive pharmaceutical ingredient is an amount sufficient to cure,prevent, reduce the risk of, alleviate or partially arrest the clinicalmanifestations of a given disease or movement disorder and itscomplications. The amount that is effective for a particular therapeuticpurpose will depend on the severity and the sort of the movementdisorder as well as on the weight and general state of the subject.

The pharmaceutical composition according to the present disclosure maybe administered one or several times per daysuch as 1 to 4 times perday, such as 1 to 3 times per day, such as 1 to 2 times per day, such as2 to 4 times per day, such as 2 to 3 times per day. In a particularembodiment, the composition is administered once a day, such as twiceper day, for example 3 times per day, such as 4 times per day.

Administration may occur for a limited time or administration may bechronic such as chronic from the onset of diagnosis, such as throughoutthe lifetime of the individual or as long as the individual will benefittherefrom i.e. when a movement disorder is present or while having anincreased risk of developing a movement disorder.

In one embodiment, the pharmaceutical composition is to be administeredas long as a movement disorder is present or as long as an increasedrisk of developing a movement disorder is present.

The concentration of each of the active pharmaceutical ingredients inthe present pharmaceutical composition; namely i) levodopa and ii) aDOPA decarboxylase inhibitor is optimized to achieve an appropriatedosage of each active pharmaceutical ingredient.

In one embodiment the pharmaceutical composition comprises levodopa inan amount of 1 mg to 1000 mg per dosage; such as about 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, 50, 100, 150, 200, 250, 300, 400, 500, 600,700, 800, 900 or 1000 mg of levodopa per dosage, wherein said dosage mayconsist of one or multiple dosage forms comprising said amount oflevodopa.

Likewise the pharmaceutical composition in one embodiment furthercomprises a DOPA decarboxylase inhibitor in an amount of 1 to 250 mg perdosage; such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75,100, 125, 150, 175, 200 or 250 mg DOPA decarboxylase inhibitor perdosage, wherein said dosage may consist of one or multiple dosage formscomprising said amount of a DOPA decarboxylase inhibitor.

In a particular embodiment the amount of levodopa in the pharmaceuticalcomposition is about 100 mg and the amount of a DOPA decarboxylaseinhibitor, such as carbidopa, is about 25 mg.

In one embodiment the pharmaceutical composition is a multiparticulatedosage form comprising

-   -   i) a first dosage form comprising about 100 mg levodopa in 10 to        50 mini-tablets, such as 20 to 40 mini-tablets, such as in about        33 mini-tablets, and    -   ii) a second dosage form comprising about 25 mg of a DOPA        decarboxylase inhibitor such as carbidopa in 5 to 15        mini-tablets, such as in about 10 mini-tablets.

Treatment of Morning Akinesia

Oral levodopa typically provides robust dependable relief of symptomswhen it is first started. However, after taking the medicine for manymonths or years, most patients with Parkinson's disease begin to developa fluctuating response to levodopa.

Fluctuating responses are divided into “ON” time, when the medication isworking well and controlling Parkinson's symptoms, and “OFF” time whenthe medication fails or is delayed in working and Parkinson's diseasesymptoms are poorly controlled. Morning akinesia is one form of “OFF”episodes. Symptoms of morning akinesia include tremor, slowness, musclestiffness, freezing and falls, and difficulty in moving and walking inthe morning.

It is an aspect to provide a pulsatile release pharmaceuticalcomposition as defined herein for use in the treatment of morningakinesia in a patient with Parkinson's disease.

It is an aspect to provide a pulsatile release pharmaceuticalcomposition comprising

-   -   i) levodopa and a DOPA decarboxylase inhibitor, and    -   ii) a pulsatile release component providing for a predetermined        lag time followed by a pulse release of said levodopa and said        DOPA decarboxylase inhibitor,

for use in the treatment of morning akinesia in a patient withParkinson's disease.

It is an aspect to provide a pharmaceutical composition comprising,separately or together,

-   -   i) a first pulsatile release component comprising levodopa, said        first pulsatile release component providing for a predetermined        lag time followed by a pulse release of levodopa, and    -   ii) a second pulsatile release component comprising a DOPA        decarboxylase inhibitor, said second pulsatile release component        providing for a predetermined lag time followed by a pulse        release of said DOPA decarboxylase inhibitor,

wherein optionally the lag time of said first pulsatile releasecomponent comprising levodopa is longer than the lag time of said secondpulsatile release component comprising a DOPA decarboxylase inhibitor,

for use in the treatment of morning akinesia in a patient withParkinson's disease.

It is an aspect to provide use of a pharmaceutical compositioncomprising, separately or together,

-   -   i) a first pulsatile release component comprising levodopa, said        first pulsatile release component providing for a predetermined        lag time followed by a pulse release of levodopa, and    -   ii) a second pulsatile release component comprising a DOPA        decarboxylase inhibitor, said second pulsatile release component        providing for a predetermined lag time followed by a pulse        release of said DOPA decarboxylase inhibitor,

wherein optionally the lag time of said first pulsatile releasecomponent comprising levodopa is longer than the lag time of said secondpulsatile release component comprising a DOPA decarboxylase inhibitor,for the manufacture of a medicament for the treatment of morningakinesia in a patient with Parkinson's disease.

In one aspect there is provided a method of treating morning akinesia ina patient with Parkinson's disease, said method comprising administeringa pharmaceutical composition comprising, separately or together,

-   -   i) a first pulsatile release component comprising levodopa, said        first pulsatile release component providing for a predetermined        lag time followed by a pulse release of levodopa, and    -   ii) a second pulsatile release component comprising a DOPA        decarboxylase inhibitor, said second pulsatile release component        providing for a predetermined lag time followed by a pulse        release of said DOPA decarboxylase inhibitor,

wherein optionally the lag time of said first pulsatile releasecomponent comprising levodopa is longer than the lag time of said secondpulsatile release component comprising a DOPA decarboxylase inhibitor.

Also provided is a pharmaceutical composition as defined herein for usein a method of a) improving the night time sleeping pattern in a patientwith Parkinson's disease; b) reducing sleep disorders involved intriggering early morning OFF periods; c) providing over-night levodopacoverage for a patient with Parkinson's disease; d) reducing OFF-time ina patient with Parkinson's disease; e) reducing dopaminergic nocturnaldecline; and/or f) increase ON-time in a patient with Parkinson'sdisease.

Also provided is a pharmaceutical composition as defined herein for usein a method of reducing motor symptoms and nonmotor symptoms associatedwith morning akinesia in a patient with Parkinson's disease.

The predominant nonmotor symptoms associated with morning akinesia areurgency of urination, anxiety, dribbling of saliva, pain, low mood, limbparesthesia, and dizziness.

Other symptoms that have been recently associated with morning akinesiainclude post-prandial bloating, abdominal discomfort, early satiety,nausea, vomiting, weight loss, and malnutrition.

The terms “treatment” and “treating” as used herein refer to themanagement and care of a patient for the purpose of combating acondition, disease or disorder. The term is intended to include the fullspectrum of treatments for a given condition from which the patient issuffering, such as administration of the composition for the purpose of:alleviating or relieving symptoms or complications; and/or preventingthe condition, disease or disorder, wherein “preventing” is to beunderstood to refer to the management and care of a patient for thepurpose of hindering the development of the condition, disease ordisorder, and includes the administration of the composition to preventor reduce the risk of the onset of symptoms or complications. Thepatient to be treated is preferably a mammal, in particular a humanbeing.

The terms “Parkinson's disease,” “Parkinson's” and “PD” refer to aneurological syndrome characterized by a dopamine deficiency, resultingfrom degenerative, vascular, or inflammatory changes in the basalganglia of the substantia nigra. This term also refers to a syndromewhich resembles Parkinson's disease, but which may or may not be causedby Parkinson's disease, such as Parkinsonian-like side effects caused bycertain antipsychotic drugs.

In one embodiment said composition is administered in a therapeuticallyeffective amount. A therapeutically effective amount as used hereinrefers to an amount sufficient to cure, alleviate, prevent, reduce therisk of, or partially arrest the clinical manifestations of a givendisease or disorder and its complications, specifically morning akinesiain a patient with Parkinson's disease.

In one embodiment said pharmaceutical composition is administered priorto sleep. In one embodiment said pharmaceutical composition isadministered once daily prior to sleep.

In one embodiment said pharmaceutical composition is administered beforebedtime. In one embodiment said pharmaceutical composition isadministered once daily before bedtime.

In one embodiment said pharmaceutical composition is administered 4 to 0hours prior to sleep, such as 4 hours to 3½ hours, such as 3½ hours to 3hours, such as 3 hours to 2½ hours, such as 2½ hours to 2 hours, such as2 hours to 1½ hours, such as 1½ hours to 1 hour, such as 1 hour to 45minutes, such as 45 minutes to 30 minutes, such as 30 minutes to 20minutes, such as 20 minutes to 15 minutes, such as 15 minutes to 10minutes, such as 10 minutes to 5 minutes, such as 5 minutes to 1 minute,such as 1 minute to 0 minutes prior to sleep.

In one embodiment said pharmaceutical composition is administered 4 to 0hours before bedtime, such as 4 hours to 3½ hours, such as 3½ hours to 3hours, such as 3 hours to 2½ hours, such as 2½ hours to 2 hours, such as2 hours to 1½ hours, such as 1½ hours to 1 hour, such as 1 hour to 45minutes, such as 45 minutes to 30 minutes, such as 30 minutes to 20minutes, such as 20 minutes to 15 minutes, such as 15 minutes to 10minutes, such as 10 minutes to 5 minutes, such as 5 minutes to 1 minute,such as 1 minute to 0 minutes before bedtime.

In one embodiment said pharmaceutical composition is administered incombination with an immediate-release levodopa product and/or acontrolled-release levodopa-product.

Further Active Pharmaceutical Ingredients

In one embodiment the pharmaceutical composition further comprises,separately or together, one or more further active pharmaceuticalingredients. Such further active pharmaceutical ingredients may bepresent in the first dosage form comprising levodopa, in the seconddosage form comprising a DOPA decarboxylase inhibitor, or in a thirddosage form.

A further active pharmaceutical ingredient in one embodiment is selectedfrom the group consisting of dopamine; dopamine receptor agonists suchas bromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine, lisuride, and derivatives thereof;catechol-O-methyl transferase (COMT) inhibitors such as for exampletolcapone and entacapone; apomorphine such as apomorphine injection;NMDA antagonists such as amatidine (Symmetrel); MAO-B inhibitors such asselegiline and rasagiline; serotonin receptor modulators; kappa opioidreceptors agonists such as TRK-820 ((E)-N-[17-cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamidemonohydrochloride); GABA modulators; modulators of neuronal potassiumchannels such as flupirtine and retigabine; and glutamate receptormodulators.

In one embodiment the pharmaceutical composition is administered incombination with other pharmaceutical compositions comprising levodopathat have immediate release and controlled release properties, toachieve a pharmacological active level of levodopa for a prolonged timesuch as approx. 1-8 hours. This will significantly reduce the dosingfrequency for the majority of Parkinson's disease patients compared withcurrently used products.

In one embodiment the pharmaceutical composition is administered incombination with an immediate release product comprising levodopa,and/or administered in combination with a controlled release productcomprising levodopa.

In one embodiment the pharmaceutical composition is administered incombination with one or more products selected from the group consistingof Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, Prolopa, Parcopa,Lodosyn, Modopar, Madopark, Neodopasol, EC-Doparyl, Aldomet, Aldoril,Dopamet and Dopegyt.

In one embodiment the pharmaceutical composition as disclosed herein,and the further active pharmaceutical ingredient, are administeredsimultaneously, separately or sequentially.

Kit of Parts

The present disclosure also provides for a kit of parts which can beuseful for treatment of morning akinesia as described herein.

A kit of parts according to the present disclosure comprises apharmaceutical composition as defined herein for treatment, preventionor alleviation of morning akinesia. Kits allows for simultaneous,sequential or separate administration of the pharmaceutical compositionand one or more further active pharmaceutical ingredients as describedherein.

EXAMPLES Example 1

Lactose was mixed with Microcrystalline cellulose, Sodium starchglycolate and a model compound (Nicotinamide) for 5 min. in a tumblemixer. Next magnesium stearate was added and mixed in for 30 sec. Themix was compressed to tablets, each tablet with a tablet weight of 6.6mg and size 2 mm each holding 0.28 mg model compound. Tablet thicknesswas around 1.7 mm.

Lactose 183.20 Microcrystalline cellulose 76.00 Sodium starch glycolatetype A 120.00 Model compound 16.80 Magnesium stearate 4.00 Total 400.00

Model compound mini-tablets were film-coated in a fluid bed with asemi-permeable film based on Ethyl cellulose. Film composition is givenin the below table. For 325 g core tablets, 1000 g of film solution wasproduced to be able to film coat to the desired increase in tabletweight of up to 25.0% incl. 10% overage for production loss. Sprayingconditions were controlled to an outlet air temperature of 28-30° C. Toreach the desired weight gain of 20%, 23% and 25%, 682.0 g, 784.9 g and853.1 g film solution was applied respectively.

Ethyl cellulose 7 cps 100.0 Ethanol 96% 900.0 Total 1000.0

44 Mini-tablets were tested for dissolution using an USP2 Paddleapparatus (USP

Paddle Dissolution Test Method). Each vessel contained 600 ml isotonicsodium chloride solution and was rotated at 75 rpm. Retrieved sampleswere quantified at a spectrophotometer at 260 nm. Results are shown inFIG. 2 .

Example 2

Mini-tablets from Example 1 were film-coated in a fluid bed with asemi-permeable film based on Ethyl cellulose. Film composition is givenin the below table. For 325 g core tablets, 1000 g of film solution wasproduced to be able to film coat to the desired increase in tabletweight of up to 25.0% incl. 10% overage for production loss. Sprayingconditions were controlled to an outlet air temperature of 28-29° C. Toreach the desired weight gain of 10%, 15%, 20% and 25%, 341.3 g, 511.9g, 682.5 g and 853.1 g film solution was applied respectively.

Ethyl cellulose 7 cps 90.0 Ethanol 96% 675.0 Polyvinyl alcohol 10.0Purified water 225.0 Total 1000.0

44 Mini-tablets were tested for dissolution using an USP2 Paddleapparatus. Each vessel contained 600 ml isotonic sodium chloridesolution and was rotated at 75 rpm. Retrieved samples were quantified ata spectrophotometer at 260 nm. Results are shown in FIG. 3A.

Example 3

Mini-tablets from Example 1 were film-coated as described in Example 2with the following film composition:

Ethyl cellulose 7 cps 76.0 Ethanol 96% 678.7 Polyvinyl alcohol 19.01Purified water 226.2 Total 1000.0

The mini-tablets were tested as described in Example 2 and the resultsgiven in FIG. 3B.

Example 4

Mini-tablets from Example 1 were film-coated as described in Example 2with the following film composition:

Ethyl cellulose 7 cps 90.0 Ethanol 96% 675.75 Hypromellose 3 9.0Purified water 225.25 Total 1000.0

The mini-tablets were tested as described in Example 2 and the resultsgiven in FIG. 4A.

Example 5

Mini-tablets from Example 1 were film-coated as described in Example 2with the following film composition:

Ethyl cellulose 7 cps 80.0 Ethanol 96% 675.0 Hypromellose 3 20.0Purified water 225.0 Total 1000.0

The mini-tablets were tested as described in Example 2 and the resultsgiven in FIG. 4B.

Example 6

Levodopa was mixed with Microcrystalline cellulose, Sodium starchglycolate and Pre-gelatinized starch for 2 min. in a 1 L high shearmixer. Purified water was added slowly over 3-4 min. while mixing untilproper humidity was achieved and then granulated for 2 min. The producedgranulate was dried at 40° C. overnight and sieved through a 0.6 mmscreen.

Levodopa 180.00 Microcrystalline cellulose 60.00 Sodium starch glycolatetype A 30.00 Pre-gelatinized starch 30.00 Purified water gs (≈160 g)Total 300.0

The produced Levodopa granulate was mixed with Sodium starch glycolateand magnesium stearate.

Levodopa granulate 277.0 Sodium starch glycolate type A 80.91 Magnesiumstearate 3.62 Total 361.53

The mix was compressed to tablets, each tablet with a tablet weight of6.15 mg and size 2 mm each holding 2.8 mg Levodopa. Tablet thickness wasaround 1.7 mm.

Composition % mg/tablet Levodopa 46.0% 2.83 Microcrystalline cellulose15.3% 0.94 Sodium starch glycolate Type A 30.0% 1.85 Pregelatinizedstarch 7.7% 0.47 Mg. Stearat 1.0% 0.06 Total 6.15

Levodopa mini-tablets were film-coated in a fluid bed with asemi-permeable film based on Ethyl cellulose. Film composition is givenin the below table. For 320 g core tablets, 900 g of film solution wasproduced to be able to film coat to the desired increase in tabletweight of up to 25.0% incl. 10% overage for production loss. Sprayingconditions were controlled to an outlet air temperature of 27-29° C. Toreach the desired weight gain of 10%, 15%, 20% and 25%, 336.0 g, 504.0g, 672.0 g and 840.0 g film solution was applied respectively.

Ethyl cellulose 7 cps 72.0 Ethanol 96% 607.5 Hypromellose 3 cps 18.0Purified water 202.5 Total 900.0

100 mg Levodopa corresponds to approx. 35 mini-tablets.

Example 7

Levodopa was mixed with Microcrystalline cellulose, Sodium starchglycolate and Pre-gelatinized starch for 2 min. in a 1 L high shearmixer. Purified water was added slowly over 3-4 min. while mixing untilproper humidity was achieved and then granulated for 2 min. The producedgranulate was dried at 40° C. overnight and sieved through a 0.6 mmscreen.

Levodopa 195.00 Microcrystalline cellulose 60.00 Sodium starch glycolatetype A 15.00 Pre-gelatinized starch 30.00 Purified water qs (≈160 g)Total 300.0

The produced Levodopa granulate was mixed with Sodium starch glycolateand magnesium stearate. The mix was compressed to tablets, each tabletwith a tablet weight of 6.4 mg and size 2 mm each holding 3.0 mgLevodopa. Tablet thickness was around 1.7 mm

Levodopa granulate 254.03 Sodium starch glycolate type A 92.47 Magnesiumstearate 3.50 Total 350.0

Levodopa mini-tablets were film-coated in a fluid bed with asemi-permeable film based on Ethyl cellulose. Film composition is givenin the below table. For 300 g core tablets, 900 g of film solution wasproduced to be able to film coat to the desired increase in tabletweight of up to 25.0% incl. 10% overage for production loss. Sprayingconditions were controlled to an outlet air temperature of 27-29° C. Toreach the desired weight gain of 17.5%, 20.0%, 22.5% and 25.0%, 551.3 g,630.0 g, 708.8 g and 787.5 g film solution was applied respectively.

Ethyl cellulose 7 cps 72.0 Ethanol 96% 607.5 Hypromellose 3 cps 18.0Purified water 202.5 Total 900.0

100 mg Levodopa corresponds to approx. 33 mini-tablets.

Example 8

Mini-tablets from Example 6 were tested for dissolution using an USP2Paddle apparatus. Mini-tablets corresponding to 100 mg Levodopa weretested in each vessel using 600 ml isotonic sodium chloride solution and75 rpm. Retrieved samples were quantified at a spectrophotometer at 284nm. Results are shown in FIG. 6 (full lines) together with results fromExample 5 (dotted lines) to demonstrate similar release from Levodopacompared to model compound.

Example 9

Mini-tablets from Example 7 were tested for dissolution using an USP2Paddle apparatus. Mini-tablets corresponding to 100 mg Levodopa weretested in each vessel using 600 ml isotonic sodium chloride solution and75 rpm. Retrieved samples were quantified at a spectrophotometer at 284nm. Results are shown in FIG. 5 .

Example 10

Levodopa was mixed with Microcrystalline cellulose, Sodium starchglycolate and Pre-gelatinized starch for 2 min. in a 1 L high shearmixer. Purified water was added slowly over 3-4 min. while mixing untilproper humidity was achieved and then granulated for 2 min. The producedgranulate was dried at 40° C. overnight and sieved through a 0.6 mmscreen.

Levodopa 225.00 Microcrystalline cellulose 30.00 Sodium starch glycolatetype A 15.00 Pre-gelatinized starch 30.00 Purified water qs (≈110 g)Total 300.0

The produced Levodopa granulate was mixed with Sodium starch glycolateand magnesium stearate. The mix was compressed to tablets, each tabletwith a tablet weight of 5.75 mg and size 2 mm each holding 4.0 mgLevodopa. Tablet thickness was around 1.6 mm

Levodopa granulate 292.22 Sodium starch glycolate type A 16.66 Magnesiumstearate 3.12 Total 312.0

Levodopa mini-tablets were film-coated in a fluid bed with asemi-permeable film as described in Example 6. 100 mg Levodopacorresponds to approx. 44 mini-tablets.

Mini-tablets were tested for dissolution as described in Example 8 andresults are given in FIG. 7 demonstrating poor control and poor burstrelease with low level super disintegrant.

Example 11

Carbidopa is mixed with Microcrystalline cellulose, Sodium starchglycolate and pre-gelatinized starch for 2 min. in a 1 L high shearmixer. Purified water is added slowly over 3-4 min. while mixing untilproper humidity was achieved and then granulated for 2 min. The producedgranulate is dried at 40° C. overnight and sieved through a 0.6 mmscreen.

Carbidopa 100.00 Microcrystalline cellulose 70.00 Sodium starchglycolate type A 10.00 Pre-gelatinized starch 20.00 Purified water qs(≈70 g) Total 200.0

The produced Carbidopa granulate is mixed with Sodium starch glycolateand magnesium stearate. The mix is compressed to tablets, each tabletwith a tablet weight of 6.90 mg and size 2 mm each holding 2.5 mgCarbidopa. Tablet thickness is around 1.9 mm.

Carbidopa granulate 217.74 Sodium starch glycolate type A 79.26Magnesium stearate 3.00 Total 300.0

Carbidopa mini-tablets are film-coated in a fluid bed with asemi-permeable film based on Ethyl cellulose. Film composition is givenin the below table. For 300 g core tablets, 900 g of film solution isproduced to be able to film coat to the desired increase in tabletweight of up to 25.0% incl. 10% overage for production loss. Sprayingconditions are controlled to an outlet air temperature of 27-29° C. Toreach the desired weight gain of 10%, 15%, 20% and 25%, 336.0 g, 504.0g, 672.0 g and 840.0 g film solution is applied respectively.

Ethyl cellulose 7 cps 72.0 Ethanol 96% 607.5 Hypromellose 3 cps 18.0Purified water 202.5 Total 900.0

25 mg Carbidopa corresponds to approx. 10 mini-tablets.

Example 12

Mini-tablets from Example 11 are tested for dissolution using an USP2Paddle apparatus. Mini-tablets corresponding to 25 mg Carbidopa aretested in each vessel using 600 ml isotonic sodium chloride solution and75 rpm. Retrieved samples are quantified at a spectrophotometer at 284nm.

Example 13

33 Levodopa mini-tablets coated to 25% weight gain from Example 7 andten film coated Carbidopa mini-tablets from Example 11 are mixed andfilled into a hard shell gelatine capsule size 0. The capsule holds adose of 100 mg Levodopa +25 mg Carbidopa and the active components willbe released after a lag-time; Carbidopa will be released followed byLevodopa.

Example 14

Morning Akinesia, Phase I PK study

A randomized, open-label, cross-over study evaluating thepharmacokinetic characteristics and relative bioavailability of singledosings of a number of selected prototype formulations containingcarbidopa and L-DOPA in healthy subjects.

The primary endpoint is to evaluate the pharmacokinetic (PK)characteristics and relative bioavailability of single dosings of anumber of selected prototype pulsatile release formulations containingcarbidopa and L-DOPA.

The following evaluations will be made:

-   -   Concentration-time data from plasma will be used to calculate        applicable PK parameters for L-DOPA and carbidopa, including        maximum plasma level (Cmax and Tmax).

Example 15

Morning Akinesia, Phase Ib, efficacy/safety and PK study

A randomized, double-blinded, placebo-controlled, cross-over studyevaluating the short term efficacy and safety as well as thepharmacokinetic characteristics of single dosing of a number of selectedprototype formulations containing carbidopa and L-DOPA in patients withParkinson's disease suffering from morning akinesia.

The primary endpoint is to evaluate the efficacy (short term) of singledosing of a number of selected prototype pulsatile release formulationscontaining carbidopa and L-DOPA.

The following evaluations will be made:

-   -   Assessment of the Parkinson's disease symptoms at morning time        when morning akinesia is usually present (by the use of the        UPDRS scale) after treatment with the selected prototype        formulations containing carbidopa and L-DOPA.

Example 10

Carbidopa was mixed with Microcrystalline cellulose, Sodium starchglycolate and Pre-gelatinized starch for 2 min. in a 1 L high shearmixer. A solution of Pre-gelatinized starch in Purified water was addedslowly over 2-3 min. while mixing until proper humidity is achieved andthen granulated for 1 min. The produced granulate is dried in a STREAfluid-bed at approx. 60° C. until water activity was below 20% andsieved through a 1.4 mm screen.

Carbidopa 75.00 Microcrystalline cellulose 31.95 Sodium starch glycolatetype A 28.05 Pre-gelatinized starch 10.00 Purified water 121Pre-gelatinized starch 5.00 Total 150.0

The produced Carbidopa granulate was mixed with Sodium starch glycolateand magnesium stearate. The mix was compressed to tablets, each tabletwith a tablet weight of approx. 7.20 mg and size 2 mm each holding 2.6mg Carbidopa. Tablet thickness was around 1.8 mm.

Carbidopa granulate 254.10 Sodium starch glycolate type A 92.49Magnesium stearate 3.50 Total 350.0

Carbidopa mini-tablets were film-coated in a fluid bed with asemi-permeable film based on Ethyl cellulose. Film composition is givenin the below table. For 300 g core tablets, 900 g of film solution wasproduced to be able to film coat to the desired increase in tabletweight of up to 25.0% incl. 5% overage for production loss. Sprayingconditions were controlled to an outlet air temperature of 27-29° C. Toreach the desired weight gain of 15%, 17.5%, 20%, 22.5% and 25%, 441.0g, 514.5 g, 588.0 g, 661.5 g and 735.0 g film solution was appliedrespectively.

Ethyl cellulose 7 cps 72.0 Ethanol 96% 607.5 Hypromellose 3 cps 18.0Purified water 202.5 Total 900.0

25 mg Carbidopa corresponds to approx. 10 mini-tablets.

Example 11

Mini-tablets from Example 16 were tested for dissolution using an USP2Paddle apparatus. Mini-tablets corresponding to 25 mg Carbidopa weretested in each vessel using 600 ml isotonic sodium chloride solution and75 rpm. Retrieved samples were quantified at a spectrophotometer at 284nm. Results are shown in FIG. 8 .

1. A pulsatile release pharmaceutical composition comprising i) levodopaand a DOPA decarboxylase inhibitor, and ii) a pulsatile releasecomponent providing for a predetermined lag time followed by a pulserelease of said levodopa and said DOPA decarboxylase inhibitor.
 2. Apulsatile release pharmaceutical composition comprising, separately ortogether, i) a first pulsatile release component comprising levodopa,said first pulsatile release component providing for a predetermined lagtime followed by a pulse release of levodopa, and ii) a second pulsatilerelease component comprising a DOPA decarboxylase inhibitor, said secondpulsatile release component providing for a predetermined lag timefollowed by a pulse release of said DOPA decarboxylase inhibitor.
 3. Apulsatile release pharmaceutical composition comprising, separately ortogether, i) a first pulsatile release component comprising levodopa,said first pulsatile release component providing for a predetermined lagtime followed by a pulse release of levodopa, and ii) a second pulsatilerelease component comprising a DOPA decarboxylase inhibitor, said secondpulsatile release component providing for a predetermined lag timefollowed by a pulse release of said DOPA decarboxylase inhibitor,wherein the lag time of said first pulsatile release componentcomprising levodopa is longer than the lag time of said second pulsatilerelease component comprising a DOPA decarboxylase inhibitor.
 4. Thepharmaceutical composition according to any of the preceding claims,wherein said DOPA decarboxylase inhibitor is selected from the groupconsisting of carbidopa, benserazide, methyldopa and DFMD(α-Difluoromethyl-DOPA), or a pharmaceutically acceptable derivativethereof.
 5. The pharmaceutical composition according to any of thepreceding claims, wherein said levodopa comprises pharmaceuticallyacceptable derivatives of levodopa, including but not limited tolevodopa pro-drugs such as levodopa methyl ester and XP21279; andmodified levodopa such as deuterated levodopa.
 6. The pharmaceuticalcomposition according to any of the preceding claims, wherein saidpulsatile release composition is a time controlled pulsatile releasesystem, including bulk-eroding systems and surface-eroding systems. 7.The pharmaceutical composition according to any of the preceding claims,wherein said pharmaceutical composition is a pharmaceutical dosage form.8. The pharmaceutical composition according to any of the precedingclaims, wherein said pharmaceutical dosage form is a solid dosage form,an oral dosage form, and/or an oral solid dosage from.
 9. Thepharmaceutical composition according to any of the preceding claims,wherein said pharmaceutical composition is a multiparticulate dosageform.
 10. The pharmaceutical composition according to any of thepreceding claims, wherein said pharmaceutical composition is amultiparticulate dosage form comprising, separately or together, twodosage forms: i) a first dosage form providing for a predetermined lagtime followed by a pulse release of levodopa, and ii) a second dosageform providing for a predetermined lag time followed by a pulse releaseof a DOPA decarboxylase inhibitor, wherein optionally the lag time ofsaid first dosage form comprising levodopa is longer than the lag timeof said second dosage form comprising a DOPA decarboxylase inhibitor.11. The pharmaceutical composition according to any of the precedingclaims, wherein said multiparticulate dosage form is packaged in acapsule, a pouch a sachet or a stick pack.
 12. The pharmaceuticalcomposition according to any of the preceding claims, wherein i) the lagtime for the pulsatile release component is adjusted to release saidlevodopa and said DOPA decarboxylase inhibitor in the small intestine,such as the lower part of the small intestine, and/or ii) the lag timefor the first pulsatile release component comprising levodopa, and thelag time for the second pulsatile release component comprising a DOPAdecarboxylase inhibitor, is adjusted to release said levodopa and saidDOPA decarboxylase inhibitor in the small intestine, such as the lowerpart of the small intestine.
 13. The pharmaceutical compositionaccording to any of the preceding claims, wherein i) the lag time forthe pulsatile release component comprising levodopa and a DOPAdecarboxylase inhibitor is between 2 to 8 hours; such as 2 to 3 hours,such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, suchas 6 to 7 hours, such as 7 to 8 hours, ii) the lag time for the firstpulsatile release component comprising levodopa is between 2 to 8 hours;such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, suchas 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, and/or iii)the lag time for the second pulsatile release component comprising aDOPA decarboxylase inhibitor is between 2 to 8 hours; such as 2 to 3hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours,such as 6 to 7 hours, such as 7 to 8 hours.
 14. The pharmaceuticalcomposition according to any of the preceding claims, wherein the lagtime of the first dosage form comprising levodopa is 5 minutes to 90minutes longer than the lag time of the second dosage form comprising aDOPA decarboxylase inhibitor; such as 5 to 10 minutes longer, such as 10to 15 minutes longer, such as 15 to 20 minutes longer, such as 20 to 25minutes longer, such as 25 to 30 minutes longer, such as 30 to 35minutes longer, such as 35 to 40 minutes longer, such as 40 to 45minutes longer, such as 45 to 50 minutes longer, such as 50 to 55minutes longer, such as 55 to 60 minutes longer, such as 60 to 65minutes longer, such as 65 to 70 minutes longer, such as 70 to 75minutes longer, such as 75 to 80 minutes longer, such as 80 to 85minutes longer, such as 85 to 90 minutes longer than the lag time of thesecond dosage form comprising a DOPA decarboxylase inhibitor.
 15. Thepharmaceutical composition according to any of the preceding claims,wherein the lag time of the first dosage form comprising levodopa is atleast 5 minutes longer than the lag time of the second dosage formcomprising a DOPA decarboxylase inhibitor, such as at least 10 minuteslonger, such as at least 15 minutes longer, such as at least 20 minuteslonger, such as at least 25 minutes longer, such as at least 30 minuteslonger, such as at least 35 minutes, such as at least 40 minutes longer,such as at least 45 minutes, such as at least 50 minutes longer, such asat least 55 minutes, such as at least 60 minutes longer than the lagtime of the second dosage form comprising a DOPA decarboxylaseinhibitor.
 16. The pharmaceutical composition according to any of thepreceding claims, wherein the pharmaceutical composition releases 70 to100% of the drug load measured at 2 to 5 hours after the lag phase, i.e.releases 70 to 100% of the levodopa and/or the DOPA decarboxylaseinhibitor measured at 2 to 5 hours after the lag phase.
 17. Thepharmaceutical composition according to any of the preceding claims,wherein said pharmaceutical dosage form is selected from the groupconsisting of a tablet, a mini-tablet, a micro-tablet, a sphere, apellet, a granule and a capsule.
 18. The pharmaceutical compositionaccording to any of the preceding claims, wherein the pharmaceuticaldosage form comprises a coating.
 19. The pharmaceutical compositionaccording to any of the preceding claims, wherein said pharmaceuticaldosage form is selected from the group consisting of a coated tablet, acoated mini-tablet, a coated micro-tablet, a coated sphere, a coatedpellet, a coated granule and a coated capsule.
 20. The pharmaceuticalcomposition according to any of the preceding claims, wherein thepharmaceutical dosage form comprise a soluble core, such as a solubleand swellable core, and a coating.
 21. The pharmaceutical compositionaccording to any of the preceding claims, wherein the coating is a filmcoating.
 22. The pharmaceutical composition according to any of thepreceding claims, wherein the coating is an insoluble coating, such asi) a semi-permeable insoluble coating, or ii) a rupturable insolublecoating.
 23. The pharmaceutical composition according to any of thepreceding claims, wherein the insoluble coating comprises a film-formingpolymer and/or a water-insoluble polymer.
 24. The pharmaceuticalcomposition according to any of the preceding claims, wherein thesemi-permeable insoluble coating comprises a water-insoluble polymer anda pore-former, such as a hydrophilic pore former.
 25. The pharmaceuticalcomposition according to any of the preceding claims, wherein the ratioin the coating of the film-forming or water-insoluble polymer and thehydrophilic pore-former is approx. 10/90, 15/85, 20/80, 25/75 or 30/70.26. The pharmaceutical composition according to any of the precedingclaims, wherein the film-forming polymer and/or a water-insolublepolymer is selected from the group consisting of ethylcellulose,hydroxypropyl cellulose, cellulose acetate, acrylic polymers, entericpolymers, hypromellose acetate succinate, shellac, vax andethylcellulose dispersions.
 27. The pharmaceutical composition accordingto any of the preceding claims, wherein the pore-former is selected fromthe group consisting of polyvinyl alcohol (PVA), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyethyleneglycol (PEG).
 28. The pharmaceutical composition according to any of thepreceding claims, wherein the coating is a soluble coating.
 29. Thepharmaceutical composition according to any of the preceding claims,wherein said pharmaceutical dosage form comprises coated tabletscomprising levodopa and/or a DOPA decarboxylase inhibitor providing fora predetermined lag time followed by a pulse release of said levodopaand said DOPA decarboxylase inhibitor.
 30. The pharmaceuticalcomposition according to any of the preceding claims, wherein saidpharmaceutical composition is a multiparticulate dosage form comprising,separately or together, i) coated tablets comprising levodopa providingfor a predetermined lag time followed by a pulse release of levodopa,and ii) coated tablets comprising a DOPA decarboxylase inhibitorproviding for a predetermined lag time followed by a pulse release of aDOPA decarboxylase inhibitor, wherein optionally the lag time of saidcoated tablets comprising levodopa is longer than the lag time of saidcoated tablets comprising a DOPA decarboxylase inhibitor.
 31. Thepharmaceutical composition according to any of the preceding claims,wherein said coated tablets are coated mini-tablets.
 32. Thepharmaceutical composition according to any of the preceding claims,wherein said coated mini-tablets are compressed to form a tablet. 33.The pharmaceutical composition according to any of the preceding claims,wherein said dosage form comprises or consists of a core and a coating,said core comprising i) levodopa and/or a DOPA decarboxylase inhibitor,ii) a superdisintegrant, iii) one or more excipients, and iv) optionallyan anti-adherent.
 34. The pharmaceutical composition according to any ofthe preceding claims, wherein said first pulsatile release component isa coated mini-tablet comprising a mini-tablet core comprising orconsisting of i) 25 to 75% w/w levodopa; such as 25 to 30%, such as 30to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50%, such as50 to 55%, such as 60 to 65%, such as 65 to 70%, such as 70 to 75% w/wlevodopa, ii) 15 to 50% w/w superdisintegrant; such as 15 to 20%, suchas 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%,such as 40 to 45%, such as 45 to 50% w/w superdisintegrant, iii) 10 to50% w/w excipients; such as 10 to 15%, such as 15 to 20%, such as 20 to25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40to 45%, such as 45 to 50% w/w excipients, and iv) 0 to 2% w/wanti-adherent; such as 0.25 to 0.50% w/w anti-adherent, such as 0.50 to0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25, such as 1.25 to 1.50,such as 1.50 to 1.75%, such as 1.75 to 2.0% w/w anti-adherent, and acoating.
 35. The pharmaceutical composition according to any of thepreceding claims, wherein said mini-tablet core comprises 1 to 5 mglevodopa, such as 1 to 1.25 mg, such as 1.25 to 1.5 mg, such as 1.5 to1.75 mg, such as 1.75 to 2 mg, such as 2 to 2.25 mg, such as 2.25 to 2.5mg, such as 2.5 to 2.75 mg, such as 2.75 to 3 mg, such as 3 to 3.25 mg,such as 3.25 to 3.5 mg, such as 3.5 to 3.75 mg, such as 3.75 to 4 mg,such as 4 to 4.25 mg, such as 4.25 to 4.5 mg, such as 4.5 to 4.75 mg,such as 4.75 to 5 mg levodopa.
 36. The pharmaceutical compositionaccording to any of the preceding claims, wherein said second pulsatilerelease component is a coated mini-tablet comprising a mini-tablet corecomprising or consisting of i) 25 to 75% w/w DOPA decarboxylaseinhibitor; such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, suchas 40 to 45%, such as 45 to 50%, such as 50 to 55%, such as 60 to 65%,such as 65 to 70%, such as 70 to 75% w/w DOPA decarboxylase inhibitor,ii) 15 to 50% w/w superdisintegrant; such as 15 to 20%, such as 20 to25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40to 45%, such as 45 to 50% w/w superdisintegrant, iii) 10 to 50% w/wexcipients; such as 10 to 15%, such as 15 to 20%, such as 20 to 25%,such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to45%, such as 45 to 50% w/w excipients, and iv) 0 to 2% w/wanti-adherent; such as 0.25 to 0.50% w/w anti-adherent, such as 0.50 to0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25, such as 1.25 to 1.50,such as 1.50 to 1.75%, such as 1.75 to 2.0% w/w anti-adherent, and acoating.
 37. The pharmaceutical composition according to any of thepreceding claims, wherein said superdisintegrant is selected from thegroup consisting of Crosslinked starch such as sodium starch glycolate,Crosslinked Cellulose such as croscarmellose sodium and low-substitutedhydroxypropylcellulose (L-HPC), Crosslinked PVP (polyvinylpyrrolidone)such as crospovidone, Crosslinked alginic acid, Soy polysaccharides,Calcium silicate, Gellan gum and Xanthan gum.
 38. The pharmaceuticalcomposition according to any of the preceding claims, wherein saidexcipients comprise of or more of the group consisting of a binder, wetbinder, filler, solid carrier, diluent, flavouring agent, solubilizer,lubricant, glidant, suspending agent, preservative, anti-adherent,wetting agent, disintegrating agent and sorbent or combinations thereof.39. The pharmaceutical composition according to any of the precedingclaims, wherein said binder is selected from the group consisting ofacacia, alginic acid, carbomers, carboxymethylcellulose sodium,carrageenan, cellulose acetate phthalate, chitosan, copovidone,dextrate, dextrin, dextrose, ethylcellulose, gelatin, guar gum,hydroyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, hydroxypropyl starch, hydroxypropylmethylcellulose (HPMC orhypromellose), methylcellulose, microcrystalline cellulose (MCC),poloxamer, polydextrose, polyethylene oxide, povidone, sodium alginate,sucrose, starch, pregelatinized starch and maltodextrin.
 40. Thepharmaceutical composition according to any of the preceding claims,wherein said excipients comprise a wet binder selected from the groupconsisting of pregelatinized starch, hydroxypropylmethylcellulose(HPMC), methylcellulose and gelatin.
 41. The pharmaceutical compositionaccording to any of the preceding claims, wherein said excipientscomprise a binder and a wet binder, such as microcrystalline cellulose(MCC) and pregelatinized starch.
 42. The pharmaceutical compositionaccording to any of the preceding claims, wherein said excipientscomprise i) 5 to 25% w/w binder, such as 5 to 7.5%, such as 7.5 to 10%,such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as17.5 to 20%, such as 20 to 22.5%, such as 22.5 to 25% w/w binder, andii) 1 to 20% w/w wet binder, such as 1 to 2.5%, such as 2.5 to 5%, suchas 5 to 7.5%, such as 7.5 to 10%, such as 10 to 12.5%, such as 12.5 to15%, such as 15 to 17.5%, such as 17.5 to 20% w/w wet binder.
 43. Thepharmaceutical composition according to any of the preceding claims,wherein said anti-adherent is selected from the group consisting ofmagnesium stearate, calcium stearate, zinc stearate, glycerylmonostearate, hydrogenated castor oil, hydrogenated vegetable oil,medium chain glycerides, palmitic acid, poloxamers, polyethyleneglycols, stearic acid and talc.
 44. The pharmaceutical compositionaccording to any of the preceding claims, wherein said mini-tablet corecomprises or consists of i) 40 to 60% w/w, such as 45 to 55% w/wlevodopa, ii) 20 to 40% w/w, such as 25 to 35% w/w sodium starchglycolate, iii) 5 to 25% w/w, such as 10 to 20% w/w microcrystallinecellulose, iv) 1 to 20% w/w, such as 5 to 10% w/w pregelatinized starch,and v) 0.5 to 1.5% w/w, such as 1% w/w Mg stearate.
 45. Thepharmaceutical composition according to any of the preceding claims,wherein the coating is applied to increase the weight of a mini-tabletcore by 10 to 40% w/w, such as 10 to 12.5%, such as 12.5 to 15%, such as15 to 17.5%, such as 17.5 to 20%, such as 20 to 22.5%, such as 22.5 to25%, such as 25 to 27.5%, such as 27.5 to 30%, such as 30 to 32.5%, suchas 32.5 to 35%, such as 35 to 37.5%, such as 37.5 to 40% w/w.
 46. Thepharmaceutical composition according to any of the preceding claims,wherein the coating is applied to increase the weight of a tablet coreby 1 to 20% w/w, such as 1 to 2.5%, such as 2.5 to 5%, such as 5 to7.5%, such as 7.5 to 10%, such as 10 to 12.5%, such as 12.5 to 15%, suchas 15 to 17.5%, such as 17.5 to 20% w/w.
 47. The pharmaceuticalcomposition according to any of the preceding claims, wherein the weightincrease of the coating of the tablet core comprising levodopa, and theweight increase of the coating of the tablet core comprising a DOPAdecarboxylase inhibitor, are adjusted in order to release levodopabefore the DOPA decarboxylase inhibitor.
 48. The pharmaceuticalcomposition according to any of the preceding claims, wherein saidcomposition further comprises, separately or together, one or morefurther active pharmaceutical ingredients.
 49. The pharmaceuticalcomposition according to any of the preceding claims, wherein saidfurther active pharmaceutical ingredient is selected from the groupconsisting of dopamine; dopamine receptor agonists such asbromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine, lisuride, and derivatives thereof;catechol-O-methyl transferase (COMT) inhibitors such as for exampletolcapone and entacapone; apomorphine such as apomorphine injection;NMDA antagonists such as amatidine (Symmetrel); MAO-B inhibitors such asselegiline and rasagiline; serotonin receptor modulators; kappa opioidreceptors agonists such as TRK-820 ((E)-N-[17-cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxmorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamidemonohydrochloride); GABA modulators; modulators of neuronal potassiumchannels such as flupirtine and retigabine; glutamate receptormodulators; an immediate release product comprising levodopa and acontrolled release product comprising levodopa.
 50. The pharmaceuticalcomposition according to any of the preceding claims, wherein saidpharmaceutical composition and said further active pharmaceuticalingredient are administered simultaneously, separately or sequentially.51. The pharmaceutical composition according to any of the precedingclaims for use in the treatment of morning akinesia in a patient withParkinson's disease.
 52. The pharmaceutical composition according to anyof the preceding claims for use in the treatment of morning akinesia ina patient with Parkinson's disease, wherein said composition isadministered prior to sleep.
 53. The pharmaceutical compositionaccording to any of the preceding claims for use in the treatment ofmorning akinesia in a patient with Parkinson's disease, wherein saidcomposition is administered in combination with an immediate releaselevodopa-product and/or a sustained release levodopa-product.